This invention relates to a method of inhibiting the production of interleukin-1 by monocytes and/or macrophages in a human in need thereof which comprises administering an effective, interleukin-1 production inhibiting amount of a 4,5-diaryl-2(substituted)imidazole or a pharmaceutically acceptable salt thereof to such human.
Lombardino, et al., U.S. Pat. No. 3,772,441, issued Nov. 13, 1973, disclose compounds of the formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein: Ar and Ar.sup.1 are each selected from furyl, thienyl, pyridyl, phenyl and substituted phenyl, wherein said substituents are selected from fluoro, chloro, bromo, and C.sub.1-4 alkoxy;
R.sup.1 is selected from H or C.sub.1-4 alkyl; and PA1 R.sup.2 is selected from trifluoromethyl, C.sub.1-4 alkyl, furyl, thienyl, pyridyl, and substituted phenyl wherein said substituents are selected from fluoro, chloro, bromo, or C.sub.1-4 alkoxy. Lombardino, et al. disclose that such compounds are antiinflammatory agents based on their activity in the carrageenan rat foot edema test. Such test is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. Lombardino, et al. also state that such compounds are useful as antiarthritic agents but there is no further statement as to how such antiarthritic activity was determined. Such a blanket statement of antiarthritic activity does not disclose that such compounds are inhibitors of IL-1 production by macrophages and/or monocytes. PA1 R.sub.1 is C.sub.1-6 alkyl or polyhalo C.sub.1-6 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, chloro or fluoro. Cherkofsky, et al. also disclose that such compounds have antiinflammatory activity as determined by the established adjuvant-induced arthritis assay in rats, immunoregulatory effects as determined by the non-established adjuvant-induced arthritis assay in rats, and analgesic activity as determined by the phenylquinone writhing test. As stated above, the established adjuvant-induced arthritis test is of no known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. The non-established adjuvant arthritis assay is useful for detecting compounds with cyclooxygenase inhibiting activity but is of no known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. The phenylquinone writhing test is useful for detecting compounds with cyclooxygenase inhibiting activity but is of no known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. PA1 R.sup.3 is H or lower alkyl; and PA1 R.sup.4 is lower alkyl. PA1 R.sub.1 is mono or polyhalo C.sub.1-4 alkyl or C.sub.1-4 alkyl; and PA1 R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, chloro or fluoro. Dupont discloses that such compounds have antiinflammatory and immunoregulatory properties based on their activity in the non-established and established adjuvant-induced arthritis assays in rats, both of which, as stated above, have no known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. PA1 R.sup.1 is C.sub.1-6 alkyl and mono- and polyhalo C.sub.1-4 alkyl; and PA1 R.sub.1 is polyfluoro C.sub.1-2 alkyl; PA1 R.sub.2 and R.sub.3 are independently selected from 2-thienyl, 3-thienyl, 3-pyridyl, 2-furyl or monsubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F, and PA1 R.sub.4 is H, PA1 one of the groups of R.sub.2 and R.sub.3 represents phenyl which is optionally substituted by halo or lower alkoxy and the other is a 6-membered heteroaromatic ring, and salts of such compounds. PA1 R.sub.1 and R.sub.2 are independently selected from pyridyl, thienyl or monosubstituted phenyl wherein said substituent is selected from chloro, fluoro or C.sub.1-4 alkoxy. PA1 Blood neutrophils PA1 Hepatic acute-phase proteins PA1 Bone resorption PA1 Cartilage breakdown PA1 Muscle proteolysis PA1 Slow-wave sleep PA1 Endothelial procoagulant PA1 Chondrocyte proteases PA1 Synovial collagenase PA1 Endothelial neutrophil adherence PA1 Neutrophil degranulation PA1 Neutrophil superoxide PA1 Interferon production PA1 Fibroblasts PA1 Glial cells PA1 Mesangial cells PA1 Synovial fibroblasts PA1 EBV B-cell lines PA1 Monocytes PA1 Neutrophils PA1 Lymphocytes PA1 Hypothalamus PA1 Cortex PA1 Skeletal muscle PA1 Dermal fibroblast PA1 Chondrocyte PA1 Macrophage/monocyte PA1 Endothelium (PGI.sub.2) PA1 Hepatic albumin synthesis PA1 Appetite PA1 Brain binding of opioids PA1 T-cell responses PA1 B-cell responses PA1 NK activity PA1 IL-2 production PA1 Lymphokine production
Lombardino, et al., J. Med. Chem., 17(11), 1182-1188 (1974) disclose compounds of the formula ##STR2## wherein Ar and Ar.sup.1 are selected from methoxyphenyl, 4-ethoxyphenyl, 2-pyridyl and 4-halophenyl; and R is selected from 4-halophenyl, CF.sub.3, phenyl and 4-methoxyphenyl. Lombardino, et al. disclose that some of such compounds have antiinflammatory activity in the carrageenan rat paw edema test which is useful for detecting compounds which are inhibitors of cyclooxygenase but is of no known utility of detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Bender, et al., J. Med. Chem., 28. 1169-1177 (1985), disclose compounds of the formula ##STR3## wherein R is methyl or ethyl, R.sup.1 is H, methyl or ethyl, R.sup.2 is 4-methoxyphenyl, and R.sup.3 is 4-methyoxyphenyl, 4-bromophenyl or 3-fluorophenyl. Bender et al. also disclose that some of such compounds have antiarthritic activity in the rat adjuvant-induced arthritis assay and immunoregulatory activity in the mouse subliminal oxazolone-induced contact sensitivity assay. The adjuvant-induced arthritis assay is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. The mouse subliminal oxazolone induced arthritis assay is useful for detecting compounds which are immunostimulants, but is of no known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Cherkofsky, et al., U.S. Pat. No. 4,190,666, issued Feb. 26, 1980 disclose compounds of the formula ##STR4## wherein: n is 0, 1 or 2;
Zauer, et al., Chem Ber, 106, 1628-1636 (1973), disclose 4,5-bis(P-chlorophenyl)-2-(methylthio)imidazole and 4,5-bis(p-methoxyphenyl)-2-methylimidazole. There is no disclosure in Zauer, et al. regarding any biological activity of such compounds.
Ferrini, et al., U.S. Pat. No. 4,308,277, issued Dec. 29, 1981, disclose compounds of the formula ##STR5## wherein:
R.sub.1 and R.sub.2 are independently selected from thienyl or monosubstituted phenyl, wherein said substituent is selected from lower alkoxy and halo;
Ferrini, et al. state that such compounds have immunoregulatory, antiinflammatory, antithrombolic and/or antinociceptive activity as exhibited by their activity in the Kaolin paw oedema assay in normal rats and adjuvantinduced arthritic assay in rats, the phenyl-p-benzoq inoneinduced writhing assay in mice, the iv administered acetic acid induced writhing assay in rats, the pulmonary embolism assay in rabbits, and an assay of inhibition of prostaglandin synthesis from arachidonic acid by spermatocystic enzymes in cattle. The kaolin paw oedema assay is useful for detecting compounds which are cyclooxygenase inhibitors, but is of no known utility in detecting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. As stated above, the phenyl-p-benzoquinone and adjuvant-induced arthritis assays are of no known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes. The iv-administered acetic acid induced writhing assay in rats is useful for detecting compounds which are cyclooxygenase inhibitors. The assay of inhibition of prostaglandin synthesis induced by spermatocystic enzymes is useful for detecting compounds which are inhibitors of the cyclooxygenase pathway. None of the acetic acid induced writhing assay, pulmonary embolism assay or the prostaglandin synthesis assay of any known utility are useful for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Dupont, Belgian patent application No. 845,074, published November 2, 1977, disclose compounds of the formula ##STR6## wherein: n is 0, 1 or 2;
Janino, et al., Bulletin of the Chemical Society of Japan, 45, 1474-1480 (1972), and White et al., J. Orq. Chem . 29, 1926-1930 (1964), disclose 2,4,5-tri(p-chlorophenyl)imidazole. There is no disclosure in either reference regarding any biological activity of this compound.
Cherkofsky, et al., U.S. Pat. No. 4,182,769, issued Jan. 8, 1980, disclose compounds of the formula ##STR7## wherein: n is 0, 1 or 2;
R.sub.2 and R.sub.3 are independently selected from monosubstituted phenyl wherein said substituent is selected from C.sub.1-4 alkoxy, Cl or F. Cherkofsky, et al. state that such compounds have antiinflammatory activity and analgesic activity as indicated by the adjuvant-induced arthritis assay in rats, which, as stated above, is of no known utility in detecting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Ferrini et al., U.S. Pat. No. 4,461,770, issued July 24, 1984, disclose compounds of the formula ##STR8## wherein at least one of the radicals R.sub.1 and R.sub.2 is a substituted or unsubstituted heteroaryl group and the other is a substituted or unsubstituted aryl group; R.sub.3 is H or lower alkyl, n is 0, 1 or 2, and R.sub.4 is substituted or unsubstituted aliphatic hydrocarbon radical, and pharmaceutically usable salts thereof. Ferrini et al. also disclose that such compounds have anti-inflammatory, anti-nociceptive and/or anti-thrombotic activity as well as an inhibitory action on prostaglandin synthesis based on their effects in the Kaolin paw oedema test, the carrageenan paw edema test, the phenyl-p-benzoquinone induced writhing assay in mice; the arachidonate induced emboly assay in rabbit lung and the in vitro inhibition of prostaglandin synthesis from arachidonic acid assay. As stated above, none of such assay systems have any known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Cherkofsky et al., U.S. Pat. No. 4,159,338, issued June 26, 1979, disclose compounds of the formula ##STR9## wherein: n is 0, 1 or 2;
and pharmaceutically acceptable acid addition salts thereof.
Cherkofsky, et al. also disclose that such compounds have antiinflammatory, antiarthritic and/or analgesic activity based on their activity in the established adjuvant induced arthritis assay in rats and in the phenylquinone writhing test in mice. As stated above, none of such assays are of any known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Bender, et al., U.S. Pat. No. 4,175,127, issued Nov. 20, 1979, disclose compounds of the formula ##STR10## wherein R.sub.3 is H, C.sub.1-6 alkyl or mono- or polyhalo C.sub.1-4 alkyl; and
R.sup.1 and R.sup.2 are the same or different, but one of which always being pyridyl, are pyridyl or monosubstituted phenyl wherein said substituent is selected from lower alkoxy, chloro, fluoro or bromo. Bender, et al. also disclose that when R.sub.3 is H, such compounds are useful only as intermediates, and when R.sub.3 is other than H, such compounds have potent antiarthritic activity based on their activity in the adjuvant-induced polyarthritis assay in rats which, as stated above, is of no known utility for detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Fitzi, et al., U.S. Pat. No. 3,940,486, issued Feb. 24, 1976, and Fitzi et al. U.S. Pat. No. 3,929,807, issued Dec. 30, 1975, disclose compounds of the formula ##STR11## wherein: R.sub.1 is halo-substituted phenyl; and
Fitzi, et al. also disclose that such compounds have antiinflammatory, antinociceptive and antipyretic action based on their activity in the Bolus alba oedema test in rats; the phenyl-p-benzoquinone-induced writhing assay in mice, and yeast-induced fever assay in rats. As stated above, such assays have no known utility in detecting or suggesting compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.
Lantos, et al., J. Med. Chem., 27(1), 72-75 (1984), disclose 4-(4-methyoxyphenyl)-5-(4-pyridyl)-2-thione-imidazole and 4-(4-fluorophenyl)-5-(4-pyridyl)-2-thione-imidazole as intermediates. There is no disclosure in Lantos, et al. regarding any biological activity of such compounds.
Cherkofsky, et al., U.S. Pat. No. 4,199,592, issued Apr. 12, 1980, discloses compounds of the formula ##STR12## wherein R.sub.3 is H; and
Cherkofsky, et al. also disclose that such compounds have antiinflammatory, antiarthritic and/or analgesic activity based on their activity in the established adjuvant-induced arthritis assay in rats and the phenylquinone induced writhing assay in mice. As stated above, none of such assays either disclose or suggest compounds which are inhibitors of IL-1 production by macrophages and/or monocytes.